1. Field of the Invention
The present invention concerns a novel human cytokine. In particular, isolated nucleic acid molecules are provided encoding interleukin-19 (IL-19). IL-19 polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. The invention further concerns therapeutic methods for modulating cytokine production.
2. Related Art
Interleukin-10 (IL-10) is a pleiotropic cytokine that has been implicated as an important regulator of the functions of lymphoid and myeloid cells. IL-10 blocks activation of cytokine synthesis and several accessory functions of macrophages, thus acting as a potent suppressor of the effector functions of macrophages, T cells and NK cells. IL-10 has also been implicated in the regulation of differentiation of B cells, mast cells and thymocytes.
IL-10 was identified independently in two different lines of experiments. One of these identified a B-cell-derived mediator which co-stimulated active thymocytes (Suda et al., Cell Immunol. 129:228 (1990)). The other identification determined that IL-10 is involved in the cross-regulation between two often mutually exclusive effector arms of immunity carried out by T helper (CD4.sup.+) subpopulations, Th1 (involved in cell-mediated immune responses) and Th2 (involved in antibody-mediated immune responses). In this role, IL-10 is expressed by Th2 cells and functions to suppress cytokine production by Th1 cells, an activity termed cytokine synthesis inhibitory factor (CSIF) activity.
cDNA clones encoding murine IL-10 (mIL-10) were isolated based on the expression of CSIF activity (Moore et al., Science 248:1230-34 (1990)). cDNA clones encoding human IL-10 (hIL-10) were subsequently identified by cross-hybridization with the mouse cDNA (Vieira et al., Proc. Natl. Acad. Sci. USA 88:1172-1176 (1991)). mIL-10 is expressed by mouse CD4.sup.+ Th2 cells, at least one CD8.sup.+ clone, B lymphomas, T cells, activated mast cell lines, activated macrophages, keratinocytes, and Ly-1 B (B-1) cells (Fiorentino, D. F. et al., J Exp. Med. 170:2081 (1989); (Moore et al., Science 248:1230-34 (1990); 87-93 (1992); Lin et al., Ann. N.Y. Acad. Sci. 651 O'Garra et al. Int. Immunol. 2: 821-832 (1990); MacNeil et al., J. Immunol. 145: 4167-4173 (1990); Fiorentino et al., J. Immunol. 147:3815-3822 (1991); Hisatsune et al, Lymphokine Cytokine Res. 11:651-683 (1992)). hIL-10 is expressed by human CD4.sup.+ T cells and Th0, Th1, and Th2 T cell clones, by CD8.sup.+ T cells and clones (Yssel et al., J. Immunol.), monocytes/macrophages, keratinocytes, activated B cells, B lymphomas, and Burkitt lymphoma lines infected with a transforming EBV strain, but not with a non-transforming strain (Vieira, P. et al., Proc. Natl. Acad. Sci. USA 88:1172-76 (1991); de Waal-Malefyt, R. et al., J. Exp. Med. 174:1209-20 (1991);de Waal-Malefyt, R. et al., J. Exp. Med. 174:915-24 (1991); Salgame, P. et al., Science 254:279-82 (1991);Yamamura, M. et al., Science 254:277-79 (1991);Ralph, P. et al., J. Immunol. 148:808-14 (1992);Benjamin, D. et al., Blood 80:1289-98 (1992)). Thus, IL-10 is not strictly a Th2-specific cytokine, and its pattern of expression resembles IL-6 more than IL-4 or IL-5 (Wang, S. C. et al., Transplant. Proc. 23:2920-22 (1991)). Like IL-6 but unlike most other T cell derived cytokines, IL-10 expression is not inhibited by cyclosporin or FK-506 (Wang, S.C. et al., Transplant Proc. 23:2920 (1991)).
In an attempt to determine the in vivo role of IL-10, normal mice were treated from birth to adulthood with IL-10--neutralizing antibodies (Wang, S. C. et al., Transplant Proc. 23:2920 (1991); Ishida, H. et al., J. Exp. Med175:1213 (1992)) The resulting phenotypic changes included an increased level of circulating IFN-.gamma., TNF-.gamma. and IL-6, reduced serum IgM and IgA, a marked depletion of peritoneal B cells, and an inability to develop in vivo antibody responses to two bacterial antigens known be combatted with antibody produced by peritoneal B cells (Hayakawa, K. et al., Annu. Rev. Immunol. 6:197 (1988)). The reduction in peritoneal B cells was determined to be a consequence of IFN-.gamma. elevation (Ishida, H. et al., J. Exp. Med. 175:1213 (1992)).
Other experiments have shown that IL-10 suppresses in vitro production of inflammatory monokines such as TNF-.alpha. and IL-1. This data corresponds to in vivo studies which show that IL-10 antagonists elevate the same inflammatory monokines. These results predict a strong anti-inflammatory role for IL-10. In addition, IL-10 antagonists may be useful to enhance Th1 immunity, which could be beneficial in infectious diseases of viral origin, or diseases involving intracellular pathogens.
The diverse biological activities of IL-10 have led to predictions that both IL-10 and its antagonists will have a wide range of clinical applications. It is clear that there is a continuing need in the art for isolating novel cytokines capable of mediating such diverse biological processes.